Declining trend in valproate use in Finland among females of childbearing age in 2012-2016 - a nationwide registry-based outpatient study.

BACKGROUND AND PURPOSE: Documented teratogenic effects of valproate (VPA) prompted restrictions of its use in females of childbearing age in 2014. We investigated possible annual changes in the outpatient use of VPA in Finland during 2008-2016 with a special focus on women. METHODS: We identified all outpatients with VPA purchases between 2008 and 2016 categorizing users due to epilepsy, bipolar disorder or miscellaneous indications. Temporal trends in the annual prevalence rates of VPA use were estimated using Poisson regression analyses. RESULTS: Between 2012 and 2016, the prevalence of VPA use among women aged 15-44 years decreased by 19%, from 50/10 000 to 40/10 000 (prevalence rate ratio, 0.81; 95% confidence intervals, 0.77-0.91; P < 0.001). The use of VPA due to epilepsy decreased significantly in females aged 15-24 and 25-34 years and that due to bipolar disorders decreased significantly in females aged 25-34 and 35-44 years. The use of VPA in the miscellaneous indication group decreased by 32% after 2014 in females aged 15-44 years and, most strikingly, by 56% among those aged 15-25 years. In women with epilepsy, the use of VPA increased among those over the age of 44 years. CONCLUSIONS: The rates of female VPA users with childbearing potential have decreased in all three major indication groups in Finland during recent years, especially after the European Medicines Agency restrictions were published in 2014. However, it still remains open to question as to whether the practice of VPA use follows current guidelines. A special concern is the relatively high prevalence of off-label use of VPA in fertile-aged females.

Idiopathic generalized epilepsies: a follow-up study in a single-center.

OBJECTIVE: To characterize adult patients with idiopathic generalized epilepsies (IGEs) with precise evaluation and to assess factors related to refractoriness. MATERIALS AND METHODS: Hospital records of all our patients with IGEs (n = 128) were evaluated in 2005 and followed-up until 2008. RESULTS: In 2005, 76% of patients were 1-year seizure-free. Seizure freedom increased to 82% during the 3-year follow-up. Seizure freedom was not significantly associated with age, age at diagnosis, epilepsy duration, exposure to inappropriate initial antiepileptic drug (AED), or delay time between starting initial AED and appropriate AED. Women constituted 78% of patients with merely provoked seizures. In 58% of women with recent seizure, one to two avoidable precipitating factors, such as lack of sleep, alcohol, and forgetting to take AED, were observed. In 2008, all patients with no medication, 91% of monotherapy patients, 60% of patients on two AED, and 14% of patients on three AED were seizure-free. CONCLUSIONS: Most of patients with IGEs can be successfully treated with monotherapy. Refractory seizures in some patients may be because of avoidable factors, especially in young women.

Interleukin-6, interleukin-1 receptor antagonist and interleukin-1beta production in patients with focal epilepsy: A video-EEG study.

UNLABELLED: Experimental and clinical studies have shown that prolonged seizures result in increased cytokine production in the central nervous system. The purpose of this study was to examine plasma concentrations of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and interleukin-1 beta (IL-1beta) in 20 patients with epilepsy undergoing a video-EEG study. Plasma samples were obtained at the onset of the recordings and 3, 6, 12 and 24 h after the index seizure. Localization of the seizure focus and classification of epilepsy was based on concordant electroclinical findings in the video-EEG study, and on MRI examination. Patients were divided into two groups: temporal lobe epilepsy (TLE) (n=11), and extratemporal lobe epilepsy (XLE) (n=9). RESULTS: Only the TLE group showed significant increase in plasma levels of IL-6 peaking at 6 h postictally. Postictal plasma levels of IL-1RA and IL-1beta did not significantly differ from baseline levels in either of the patient groups. IL-1RA showed a decreasing trend (p>0.059) in TLE patients during 12 to 24 postictal hours. CONCLUSIONS: This study further supports the role of focal seizures in regulation of cytokine responses.

Hippocampal sclerosis in refractory temporal lobe epilepsy is associated with gluten sensitivity.

BACKGROUND: Previous studies have associated coeliac disease (CD) and gluten sensitivity (defined as the presence of anti-gliadin antibodies and positive immunogenetics) with cerebellar degeneration and epilepsy with occipital calcifications. Hippocampal sclerosis (HS) in temporal lobe epilepsy (TLE) is a potentially progressive disorder with unknown aetiology; however, autoimmunity has been implicated as one of the possible mechanisms leading to HS. The purpose of this study is to analyze CD-associated antibodies and gluten sensitivity in a well-characterised group of patients with refractory focal epilepsy. METHODS: We measured anti-gliadin, anti-tissue-transglutaminase and anti-endomysium antibodies, and coeliac-type human leukocyte antigen (DQ2 and DQ8), in 48 consecutive patients with therapy-resistant, localisation-related epilepsy. The patients were categorised into the following three groups on the basis of ictal electro-clinical characteristics and the findings of high resolution MRI: TLE with HS (n = 16), TLE without HS (n = 16) and extratemporal epilepsy (n = 16). Patients with suspected CD or gluten sensitivity underwent duodenal biopsies. RESULTS: Seven patients in total were gluten sensitive; all of these patients fell in the TLE with HS group. On the other hand, none of the TLE without HS patients or those with extratemporal epilepsy were gluten sensitive (p<0.0002). The results of duodenal biopsies showed that three of the seven gluten-sensitive patients had histological evidence of CD and four had inflammatory changes consistent with early CD without villous atrophy. Four of the patients with gluten sensitivity had evidence of dual pathology (HS+another brain lesion), whereas none of the remaining patients did (p<0.0002). CONCLUSIONS: The present study demonstrates a previously unrecognised link between gluten sensitivity and TLE with HS. This association was very robust in this well-characterised group of patients; thus gluten sensitivity should be added to the list of potential mechanisms leading to intractable epilepsy and HS.

Retention rates of new antiepileptic drugs in localization-related epilepsy: a single-center study.

OBJECTIVES: We evaluated long-term retention rates of newer antiepileptic drugs (AED) in adults with localization-related epilepsy retrospectively. METHODS: We estimated retention rates by Kaplan-Meier method in all 222 patients (age > or = 16) with localization-related epilepsy exposed to new AED at the Tampere University Hospital. RESULTS: There were 141 patients exposed to lamotrigine, 78 to levetiracetam, 97 to topiramate, 68 to gabapentin, and 69 to tiagabine. Three-year retention rate for lamotrigine was 73.5%, levetiracetam 65.4%, topiramate 64.2%, gabapentin 41.7%, and tiagabine 38.2%. The most common cause for withdrawal of these AED was lack of efficacy. CONCLUSIONS: Our study suggests that there are clinically significant differences among gabapentin, lamotrigine, levetiracetam, tiagabine, and topiramate as treatment for focal epilepsy in everyday practice. Gabapentin and tiagabine seem to be less useful than the other three AED. Furthermore, our study supports the value of retention rate studies in assessing outcome of the drugs in clinical practice.

Clinical predictors in patients with refractory epilepsy exposed to levetiracetam: a single-center study.

OBJECTIVES: This aim of the study was to ascertain the importance of clinical parameters on the response to treatment in refractory epilepsy patients on levetiracetam (LEV). MATERIALS AND METHODS: We retrospectively evaluated medical records of 132 patients aged 17-78 years with refractory epilepsy (defined as a failure of at least two antiepileptic drugs due to the lack of efficacy) exposed to LEV. We analyzed the response (seizure freedom or continuing LEV) using logistic regression. RESULTS: Of 132 patients exposed to LEV, 103 cases continued the drug. Of the discontinuations (29/132), 75% were for lack of efficacy and 25% for tolerability problems. Twenty-three percent of the previously refractory patients achieved seizure freedom for at least 1 year with LEV in combination therapy. The dose of LEV in 80% of seizure-free patients was 1000 mg/day or less. The duration of epilepsy, age and sex were not associated with response to LEV. Seizure freedom was associated with epileptic syndrome or etiology. If no specific syndrome was recognized, there was a significantly greater chance for response compared with temporal lobe epilepsy (OR 20.76; 95% CI 2.12-203.61). CONCLUSIONS: Our study was based on the careful clinical evaluation of the patients with extensive use of video EEG (50%) and MRI scans (95%). These clinical predictors were evasive in previous studies. This study showed that they are worth pursuing but significantly larger groups of patients need to be investigated to reach significant findings.

Increased plasma levels of cytokines after seizures in localization-related epilepsy.

OBJECTIVES: Experimental studies suggest increased cerebral production of inflammatory cytokines after prolonged seizures. Whether a single non-prolonged seizure in human patients is associated with activation of cytokine network is still unknown. MATERIALS AND METHODS: We studied the levels of interleukin-1beta (IL-1beta), interleukin-1 receptor antagonist (IL-1ra), interlukin-6 (IL-6) and soluble IL-6 receptors (sIL-6R and Gp130) in plasma after single seizures during video-EEG recordings in patients with chronic localization-related epilepsy. RESULTS: The levels of IL-1ra and IL-6 were increased after seizures, whereas IL-1beta and IL-6 cytokine receptors remained unchanged. CONCLUSIONS: These results show that only single seizures cause activation of cytokine cascade and associated inflammatory signals. In the case of recurrent seizures, these signals may result in structural changes in the nervous tissue, which are generally associated with drug refractory epilepsy.

Factors related to top running speed and economy.

The main purpose of the present study was to investigate the relationships between running mechanics, top running speed and economy in young endurance athletes. Twenty five endurance athletes (age 19.8 +/- 1.1 years, stature 1.82 +/- 0.07 m and body mass 69.4 +/- 7.5 kg) performed two separate tests on an indoor track. The first test was 8 x 30 m with increasing speed, and the second test was incremental 5 - 6 x 1,000 m. In the first test, ground reaction forces and stride characteristics were measured from each running speed. In the second test, running economy at the speed of 3.89 m . s (-1) and maximal oxygen uptake were determined. Ground contact time was the only factor which correlated significantly with both running economy (r = 0.49, p < 0.05) and maximal running speed (r = - 0.52, p < 0.01). Furthermore, maximal running speed was correlated significantly with the mass-specific horizontal force (r = 0.56, p < 0.01) but not with the vertical effective force. It is concluded that the short contact times required in economical and high speed running suggests that fast force production is important for both economical running and high top running speed in distance runners.

Regulation of IL-6 system in cerebrospinal fluid and serum compartments by seizures: the effect of seizure type and duration.

Experimental studies suggest that cytokine production may be triggered by seizure activity. Here we determined the levels of interleukin-6 (IL-6) and its soluble receptor components (sIL-6R and sGp130) in CSF and serum from control subjects and patients after different types of seizures. IL-6 levels were increased after seizures, whereas sIL-6R levels were decreased. Interestingly, the levels of IL-6 were strongly increased after recurrent generalized tonic-clonic seizures (GTCS), whereas after single tonic-clonic or prolonged partial seizures IL-6 levels were increased to lesser extent. These results provide further support for a hypothesis of cytokine production induced by seizure activity per se.

Economic burden and quality of life impairment increase with severity of PD.

PURPOSE: To define the interrelationship between cost-of-illness, quality of life (QoL) and Parkinson's disease (PD) severity in a common patient management setting in Finland.Scope. Two hundred and sixty consecutive outpatients with idiopathic PD participated. UPDRS, motor fluctuations, QoL, and the use of health care resources were measured. Direct and indirect costs were calculated. CONCLUSIONS: There is a strong relationship between QoL or cost-of-illness on the one hand, and severity of PD on the other. Treatment policies capable of reducing or delaying motor fluctuations would be expected to increase QoL and reduce some of the economic burden of PD.

Expression of cytokines and cytokine receptors in the rat brain after kainic acid-induced seizures.

We have previously shown that IL-6 protein levels are increased in cerebrospinal fluid in humans after recent tonic-clonic seizures with unchanged levels of IL-1beta and TNFalpha. Here we studied the expression of cytokines IL-6, LIF, IL-1beta and TNFalpha and cytokine receptors IL-6R, LIFR and Gp130 in the rat brain after kainic acid-induced status epilepticus using Northern blot analysis and in situ hybridization histochemistry. After seizures, IL-6 mRNA was induced in the hippocampus, cortex, amygdala and meninges, and IL-6R was up-regulated in the hippocampus. LIF was up-regulated in the hippocampus, cortex and meninges after seizures, and LIFR mRNA was induced in the hippocampus and cortex. Gp130 was constitutively expressed in the brain. After seizures, Gp130 transcription was rapidly induced in the meninges. In thalamus, cortex, amygdala and hippocampus Gp130 mRNA was induced in a delayed fashion. IL-1beta transcription was induced in the temporal lobe cortex and thalamus, and TNFalpha in the hippocampus. In general, the cytokine and their receptor mRNA levels were low in intact rat brain, but were induced by seizures. Since IL-6 and LIF transcripts were induced in the meninges after seizures, the protein products of these transcripts may be more readily released in cerebrospinal fluid after seizures. In addition, the activity of IL-6 and LIF signaling pathways may be influenced by increased expression of their receptors after seizures.

Indicators of inflammation after recent tonic-clonic epileptic seizures correlate with plasma interleukin-6 levels.

Cerebrospinal fluid (CSF) and peripheral blood pleocytosis have been observed after epileptic seizures without any evidence of infections, but no systematic studies on the acute phase reaction in such patients have been performed. We have previously reported increased levels of interleukin-6 (IL-6) in patients with recent tonic--clonic seizures. Because IL-6 is a major inducer of the systemic acute phase reaction, we decided to study various indicators of inflammation in the blood as well as their correlation with plasma and CSF IL-6 levels. CSF and blood samples were studied from 37 patients with previously undiagnosed and untreated tonic-clonic seizures without any clinical evidence of systemic or central nervous system infections as well as from 40 controls. The mean peripheral blood and CSF-leukocyte counts were significantly higher in patients compared with controls ( 7.9 x 10(9)vs. 6.1 x 10(9), P= 0.002 and 1.9 x 10(6)vs. 1.1 x 10(6), P= 0.032, respectively). There was some indication of increased concentration of C-reactive protein (CRP) and no difference in haptoglobin levels. There was a significant correlation between plasma but not CSF IL-6 concentration and those of both B-leukocyte count ( r= 0.051, P= 0.009) and CRP ( r= 0.42, P= 0.009). Epileptic seizures provoke a production of cytokines such as IL-6 that may in turn cause an activation of the acute phase reaction. Thus, CSF pleocytosis and increase in some indicators of inflammation should not automatically be attributed to systemic or CNS infections in patients with acute seizures.

High prevalence of antiphospholipid antibodies in children with epilepsy: a controlled study of 50 cases.

Evidence of immune system aberrations in patients with epilepsy includes antiphospholipid antibody positivity in adult patients with epilepsy with a prevalence of 19-26% and in 13% of children with partial epilepsy. Also immunoglobulin A deficiency has been reported to exist in up to 25% of epilepsy patients. The possible role of immune mechanisms in the pathogenesis of childhood epilepsy is clinically supported by the effectiveness of immunomodulatory treatments in cases with catastrophic childhood epilepsies. We analyzed a set of various autoantibodies in 50 consecutive children with epilepsy and in 20 healthy control subjects. None of the children had any clinical signs of immune system disorders. The main result was a significantly (P=0.011) higher prevalence of antiphospholipid antibodies in the study group (44%) compared with controls (10%). These antibodies were unexpectedly common (71-80%) in children with multiple seizure types associated often with symptomatic etiology, early onset and high frequency of seizures. There was no evidence of the antiphospholipid positivity being induced by certain AEDs (e.g. phenytoin or carbamazepine). Even though the significance of these autoantibodies remains unknown, their increased prevalence indicates that immune system mediated mechanisms may have a role in the manifestation of epilepsy in some children.

Normal CSF neuron-specific enolase and S-100 protein levels in patients with recent non-complicated tonic-clonic seizures.

PURPOSE: Increased concentrations of the nervous-system-specific proteins neuron-specific enolase (NSE) and S-100 protein (S-100) have been measured with lesions in the CNS. Elevated levels of serum NSE (s-NSE) have been found in status epilepticus, but also after single epileptic seizures. Because larger studies addressing cerebrospinal fluid (CSF) levels of NSE or S-100 have not been performed, we measured CSF NSE and S-100 after tonic-clonic seizures to search for evidence of neuronal and glial damage. METHODS: 22 consecutive patients with single, previously undiagnosed and untreated tonic-clonic seizures were studied. Serum and CSF samples were collected within 24 h after seizure. 18 serum and CSF samples were measured from a control group. RESULTS: The mean CSF NSE was 8.9 ng/ml (range 0-28 ng/ml) and s-NSE 8.2 ng/ml (range 5-15 ng/ml) in the patient group. The mean concentrations in the control group were 13.1 ng/ml (range 3-24 ng/ml) and 8.0 ng/ml (range 5-12 ng/ml) respectively. The mean CSF S-100 was 3.17 microg/l (range 1.45-7.02 microg/l) and serum S-100 0.05 microg/l (range 0-0.32 microg/l), and in controls 3.19 microg/l (range 1.52-5.13 microg/l) and 0.08 microg/l (range 0-0.28 microg/l). CONCLUSION: There were no significant differences between the mean concentrations of NSE or S-100 in CSF and serum between the epileptic group and controls. These results do not confirm the previous observation of elevated NSE-levels after tonic-clonic seizures, which argues against neuronal or glial damage after uncomplicated tonic-clonic seizures in unmedicated patients.